The filoviruses Ebola (EBOV) and Marburg (MARV) cause the most severe hemorrhagic fevers in humans with the mortality rates up to 90% and are considered potential weapons for bioterrorism and biological warfare. Recently published studies demonstrated a successful protection of rodents and nonhuman primates (NHP) against filoviruses by passively transferred polyclonal antibodies (Abs) and mouse monoclonal antibodies (mAbs). However, fully human mAbs have important advantages over murine, chimeric, or humanized mAbs that include their safety and greater potency. The central hypothesis of this proposal is that survivors of EBOV and MARV Infections likely possess circulating B cells encoding naturally-occurring human Abs that neutralize virus and protect against disease. This hypothesis is supported by a recent progress of the research team included in the application in isolation of human mAbs from a survivor of MARV infection. The key requirements for successful treatment of filovirus infections with mAbs may include (A) use of high-affinity mAbs, and (B) administration of a cocktail of mAbs binding to the diverse viral epitopes, rather than an individual mAb. This possibility will be tested by generation of comprehensive reagents for study of filovirus recognition by human Abs which will be used for pursuing the following Specific Aims: 1) To isolate large panels of human mAbs to EBOV and MARV from the B cells of humans following natural infection; 2) To identify and characterize the most potent neutralizing and cross neutralizing human mAbs; 3) To test and optimize protection of human mAbs in rodents and NHP; 4) To test post-exposure treatment of NHPs with human mAbs in combination with recombinant VSV-vectored vaccines from RPI and anti-filovirus small interfering RNA (siRNA) from RP2. This proposal incorporates experts in molecular immunology, molecular virology, viral pathogenesis and public health, with access to BSL-4 facilities. We have access to blood of survivors of all five filovirus species highly pathogenic for humans {Zaire ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus, Ivory Coast ebolavirus, and MARV) in Gabon, Democratic Republic of Congo and Uganda, that is important due to the significant antigenic diversity between the individual species of filoviruses, and blood of individuals seropositive for EBOV infection who did not experience disease. The proposed research Is significant because it will result in generation of large panels of human mAbs that neutralize EBOV or MARV, identify the most potent mAbs and test them in rodents and NHPs on their own and in combination with the other post-exposure treatments included in the CETR.